Regulation of insulin action and pancreatic β-cell function by mutated alleles of the gene encoding forkhead transcription factor Foxo1

Type 2 diabetes results from impaired action and secretion of insulin. It is not known whether the two defects share a common pathogenesis. We show that haploinsufficiency of the Foxo1 gene, encoding a forkhead transcription factor (forkhead box transcription factor O1), restores insulin sensitivity...

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Veröffentlicht in:Nature genetics 2002-10, Vol.32 (2), p.245-253
Hauptverfasser: Accili, Domenico, Nakae, Jun, Biggs, William H, Kitamura, Tadahiro, Cavenee, Webster K, Wright, Christopher V.E, Arden, Karen C
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container_issue 2
container_start_page 245
container_title Nature genetics
container_volume 32
creator Accili, Domenico
Nakae, Jun
Biggs, William H
Kitamura, Tadahiro
Cavenee, Webster K
Wright, Christopher V.E
Arden, Karen C
description Type 2 diabetes results from impaired action and secretion of insulin. It is not known whether the two defects share a common pathogenesis. We show that haploinsufficiency of the Foxo1 gene, encoding a forkhead transcription factor (forkhead box transcription factor O1), restores insulin sensitivity and rescues the diabetic phenotype in insulin-resistant mice by reducing hepatic expression of glucogenetic genes and increasing adipocyte expression of insulin-sensitizing genes. Conversely, a gain-of-function Foxo1 mutation targeted to liver and pancreatic beta-cells results in diabetes arising from a combination of increased hepatic glucose production and impaired beta-cell compensation due to decreased Pdx1 expression. These data indicate that Foxo1 is a negative regulator of insulin sensitivity in liver, adipocytes and pancreatic beta-cells. Impaired insulin signaling to Foxo1 provides a unifying mechanism for the common metabolic abnormalities of type 2 diabetes.NOTE: In the AOP version of this article, the name of the fourth author was misspelled as W K Cavanee rather than the correct spelling: W K Cavenee. This has been corrected in the full-text online version of the article. The name will appear correctly in the print version.
doi_str_mv 10.1038/ng890
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It is not known whether the two defects share a common pathogenesis. We show that haploinsufficiency of the Foxo1 gene, encoding a forkhead transcription factor (forkhead box transcription factor O1), restores insulin sensitivity and rescues the diabetic phenotype in insulin-resistant mice by reducing hepatic expression of glucogenetic genes and increasing adipocyte expression of insulin-sensitizing genes. Conversely, a gain-of-function Foxo1 mutation targeted to liver and pancreatic beta-cells results in diabetes arising from a combination of increased hepatic glucose production and impaired beta-cell compensation due to decreased Pdx1 expression. These data indicate that Foxo1 is a negative regulator of insulin sensitivity in liver, adipocytes and pancreatic beta-cells. Impaired insulin signaling to Foxo1 provides a unifying mechanism for the common metabolic abnormalities of type 2 diabetes.NOTE: In the AOP version of this article, the name of the fourth author was misspelled as W K Cavanee rather than the correct spelling: W K Cavenee. This has been corrected in the full-text online version of the article. 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subjects Animals
Biological and medical sciences
Blotting, Northern
Complications and side effects
Diabetes
Diabetes Mellitus, Experimental - genetics
Diabetes Mellitus, Experimental - metabolism
Diabetes Mellitus, Type 2 - etiology
Diabetes Mellitus, Type 2 - genetics
Diabetes Mellitus, Type 2 - metabolism
Diagnosis
Forkhead Box Protein O1
Forkhead Transcription Factors
Fundamental and applied biological sciences. Psychology
Gene expression
Gene mutations
Genetic aspects
Identification and classification
Immunohistochemistry
Insulin - physiology
Insulin resistance
Insulin Resistance - genetics
Islets of Langerhans - physiology
Liver - metabolism
Mice
Mice, Transgenic
Molecular and cellular biology
Molecular genetics
Mutation
Organ Specificity
Receptor, Insulin - genetics
Risk factors
Transcription Factors - genetics
Transcription Factors - physiology
Transcription. Transcription factor. Splicing. Rna processing
title Regulation of insulin action and pancreatic β-cell function by mutated alleles of the gene encoding forkhead transcription factor Foxo1
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